Metabolic syndrome is becoming one of the most significant health issues of modern times, predisposing individuals to diabetes and cardiovascular disease. Although considerable advances have been made in identifying genetic contributions to this syndrome, we still understand very little about the mechanisms that regulate development and progression of the disease, particularly at the epigenetic level. Genetic studies of complex diseases like metabolic syndrome, are further complicated by an array of phenotypes that likely associate with the severity or progression of the disease. By using an approach that focuses not only on disease status but also on the phenotypes that characterize a complex disorder, we can achieve a much greater power to explore the molecular pathogenesis underlying the disease. This project will use such an approach to investigate the methylation status in more than 27,000 CpG sites within approximately 14,000 genes in a large-scale study designed to identify epigenetic changes associated with metabolic syndrome and related phenotypes. Genomic methylation of CpG islands within the promoter and 5' region of a gene typically causes silencing of that gene, which is a reversible effect. This type of epigenetic aberration is recognized in a number of complex diseases, including cancer, autoimmune disorders, psychiatric disorders and most recently metabolic disorders. Few studies have investigated genomic methylation in metabolic syndrome and associated disorders, but there is evidence to suggest that it may play a strong role in the development of such disorders. This project endeavors to uncover the role of genomic methylation in metabolic syndrome and related phenotypes by: 1) determining the genomic methylation profile of 27,578 CpG sites in 1,200 Mexican Americans; 2) assessing methylation as a quantitative trait and determining correlations with metabolic syndrome phenotypes; 3) characterizing entire CpG islands of selective metabolic syndrome candidate genes; 4) verifying CpG island characteristics of selective metabolic syndrome candidate genes in two additional populations; 5) performing functional analyses to determine downstream consequences of genomic methylation in selected metabolic syndrome candidate genes. We anticipate that this project will yield a wealth of information on the role of epigenetic variation associated with metabolic syndrome and its' related phenotypes, which will have important implications relating to cardiovascular disease and diabetes. By investigating the underlying biology of complex disorders, such as metabolic syndrome, diabetes and cardiovascular disease, we can identify biomarkers that may aid in diagnosis and prognosis and better identify targets for potential therapeutic intervention. PUBLIC HEALTH RELEVANCE: The escalating prevalence of metabolic syndrome, which predicts risk for diabetes and cardiovascular disease, is of major concern due to the extremely high mortality and morbidity associated with its' consequential diseases. In this project we will undertake large-scale genomic methylation profiling in a large population of Mexican Americans from extended pedigrees to investigate potential implications for metabolic syndrome and related phenotypes. Additional comprehensive characterization of this epigenetic mechanism will contribute immensely to understanding the molecular pathology associated with metabolic syndrome.